Telomeres

Abstract

Telomeres are specialized DNA‐protein structures that occur at the ends of eukaryotic chromosomes. A special ribonucleoprotein
enzyme called telomerase is required for the synthesis and maintenance of telomeric DNA.

Model
for the role of telomerase in the replication of linear chromosomal DNA
termini in eukaryotes. (a) During the chromosomal DNA replication phase of the
cell cycle (S phase), a DNA replication fork initiated from a replication
origin within the chromosome moves toward the chromosomal DNA terminus. The
helicase associated with the replication complex unwinds (curved arrow) the
parental strands (marked A and B). (b) The transiently free single‐stranded
G‐rich DNA 3′ terminus of strand A is extended by telomerase (thick
arrow). In vitro, telomerase requires a single‐stranded 3′ end
of DNA as a primer, because the 3′ end of the primer to be elongated is
normally base‐paired to the RNA template sequence. It is thought that
telomerase acts during the S phase, perhaps using the opportunity afforded by
the displacement of the complementary strand. Leading strand synthesis (lower
rightward arrow) toward the chromosomal terminus copies all the way to the end
of parental strand B, producing one full‐length daughter DNA. (c) It has been
suggested that an as yet unidentified DNA‐processing activity produces the
3′ overhang at the telomere by nucleolytic removal of the terminal
portion of the C‐rich telomeric DNA strand. The G‐rich strand A, including its
newly extended terminus, is copied by discontinuous lagging strand synthesis
(zig‐zag is RNA primer) by the primase‐polymerase‐mediated discontinuous
synthesis typical of semiconservative DNA replication mechanisms. Removal of
the most distal RNA primer leaves a 5′ terminal gap, i.e. the protruding
G‐rich strand 3′ overhang.

Figure 2.

Polymerization
of telomeric DNA by telomerase from the ciliated protozoan Tetrahymena. (a) The 3′ nucleotides of the G‐rich primer (red) base pair with the template region of the telomerase RNA, whose ribo A
and ribo C nucleotide residues are shown. (b) The G‐rich primer is elongated, copying the telomerase RNA template, making
first round DNA extension products (lower case letters). (c) After copying the last (5′ end) of the telomerase RNA template,
the product can translocate and reposition for a second round of synthesis.

Figure 3.

An example
of the conserved core secondary structure of telomerase RNA of ciliated protozoa. The sequence of the templating domain nucleotides
in Tetrahymena telomerase RNA is indicated (AACCCCAAC) and nucleotide numbers from the 5′ end of the RNA are indicated. The conserved double‐stranded
RNA structures are shown as ladders marked I and IV, and the two helical components of the pseudoknot are ladders indicated
as a and b. Adapted from Blackburn (1998).